title: Potential roles of metallothioneins I and II in protecting bone growth following acute methotrexate chemotherapy.
abstract: Metallothioneins (MTs) are known to participate in protection against oxidative stress. This study assessed the effects of MT-I&II gene knockout on methotrexate (MTX)-induced bone damage in growing mice. MT-I&II knockout (MT⁻/⁻) and wild type (MT⁺/⁺) male mice were injected with saline or 12.5 mg kg⁻¹ MTX for three consecutive days. MTX treatment was shown to cause more severe damage in MT⁻/⁻ mice when compared to MT⁺/⁺ mice, as demonstrated by the more obvious thinning of growth plate, reduced proliferation and increased apoptosis of chondrocytes, and reduced metaphysis heights in the knockout mice. Analysis of total liver glutathione (the most abundant intracellular antioxidant) also revealed significant lower glutathione levels in all MT⁻/⁻ mice. In conclusion, MT⁻/⁻ mice were more susceptible than MT⁺/⁺ mice to MTX-induced bone damages, which may be associated with the reduction of basal antioxidant defence, suggesting a protective role of MTs in the growing skeleton against damages caused by MTX chemotherapy.
authors.forename: Chiaming
authors.initials: C
authors.lastname: Fan
authors.forename: Maria
authors.initials: M
authors.lastname: Garcia
authors.forename: Michaela
authors.initials: M
authors.lastname: Scherer
authors.forename: Cuong
authors.initials: C
authors.lastname: Tran
authors.forename: Cory J
authors.initials: CJ
authors.lastname: Xian
mesh_terms: D000208:Acute Disease; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001846:Bone Development / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006132:Growth Plate / Q000187:drug effects*; D008297:Male; D008668:Metallothionein / Q000502:physiology*; D008727:Methotrexate / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000964:Antimetabolites, Antineoplastic; D000975:Antioxidants; D012333:RNA, Messenger; D008668:Metallothionein; D005978:Glutathione; D008727:Methotrexate
keywords: Apoptosis,; Bone growth,; Cancer chemotherapy,; Growth plate,; Oxidative stress,; Proliferation